There's no shortage of "What's Wrong With the Drug Industry" article these days. I wanted to call attention to another one that's just appeared in JPET. I don't agree with all of it, but it does make some important points.
If I had to give a one-line summary of its thesis, it would be "Drug discovery forgot pharmacology and lost its way". The author, Michael Williams of Northwestern (and of 35 years at Merck, Novartis, Abbott, and Cephalon) is a pharmacologist himself, and feels that the genomics era (and indeed, the whole target-driven molecular biology era) has a lot to answer for. He also thinks that people have become seduced by technology:
Rather than creating synergies by using multiple complementary
technologies to find answers to discrete questions in a focused and coherent manner, technology-driven drug discovery has become a discipline that justifies its existence by searching for questions. An example of this is the proteomics approach to target validation, where the intrinsic complexity of the protein component of a cell or tissue necessitates a reductionistic approach where experimental samples must be separated into bins to facilitate analysis with timelines for data generation that can stretch into months or years.
To those with a technology bent, new iterations on a technology, regardless of its utility, inevitably become “must haves,” with acquisition and implementation becoming ends unto themselves. . .
One place I disagree with him is in his assertion that "Implicit in the HTS/combinatorial chemistry paradigm was/is that each target was equally facile as a starting point for a drug discovery project". That hasn't been my experience at all - there's always been a lot of arguing about which targets should be taken to screening and of what kind (how many GPCRs versus enzymes versus what-have you). Williams makes his point in the context of the genomics frenzy, when it was thought that all kinds of targets would be emerging. But at least where I worked, the hope was that genomics would provide a lot of good, tractable target that we hadn't known about, rather than just a long list of orphan receptors and whatzitases. (Mind you, that list is exactly what we ended u with).
Williams then discusses the problem of whether some targets are, in the end, truly intractable. The "just one more whack at it, and we'll get there" approach sometimes works, but it does try the patience:
Drugs active at opioid receptors remain the gold standard of analgesic care and include morphine, codeine, and oxycodone. With the discovery of the mu, delta, and kappa receptor subtypes in the 1970s, it was anticipated that development of selective agonists for these receptors would result in drugs that had a reduced liability for the respiratory depression, tolerance, constipation, and addiction associated with classical opioids. Some 40 years later, despite considerable efforts in medicinal chemistry and molecular biology to refine/define the structural characteristics of receptor-selective NCEs, the ”holy grail” of side effect-free opioids appears as elusive as ever, with a multitude of compounds showing compelling preclinical data but failing to demonstrate these properties in the clinic. . .
Another of his examples in this line are the muscarinic ligands, which I know from personal experience, as a search of my name through the literature and patent databases will show. And although GPCRs are among the most valuable target classes of all, we still have to face up to some disturbing facts about them:
Thus, for both of these G protein-coupled receptor families, a major question is whether their function is so critical, nuanced, and complex as to preclude advances based on the molecular approaches currently being used that may lack the necessary heuristic relationship to the complexity/redundancies of the systems present in a more physiological or disease-related milieu. Based on progress over the past 40 years, it may well be concluded that the opioid and muscarinic receptor families represent intractable targets in the search for improved small-molecule therapeutics. But maybe the next NCE….???
At the end of the article is a table of possible approaches to get out of the preclinical swamp. Interestingly, it's noted that it was "generated at the request of one of the reviewers", who probably asked what the author proposed to do about all this. I won't reproduce it all here, but it boils down to being more rigorous about data and statistics, using the hardest, most real-world models, and giving people the time to pursue these approaches even if they're going against the crowd while doing so. I don't see any his recommendations that I disagree with, but (and this isn't his fault), I don't see any of them that I haven't seen before, either. There needs no ghost, my lord, come from the grave, to tell us this.